Summary. DNA can be targeted by the CRISPR- Cas (CC) genome editing tool, which was swiftly implemented in anti-HIV studies1-8. We confirmed potent HIV inhibition, but also demonstrated rapid virus escape from CC attack9. Inspection of the escape viruses indicated a role of the NHEJ enzyme, which repairs dsDNA breaks and introduces small insertions/deletions (indels) in the process. In other words, we described a novel viral escape route that is facilitated by a cellular DNA repair process. These results were confirmed by other labs10-21. A combinatorial CC attack against conserved sequences triggered HIV inactivation through hypermutation, quite different from the proposed excision route (Fig 1). Although provirus excision could be detected in our system, it occurred with a very low efficiency. Instead, CC attack generated hypermutated proviruses that apparently lost all replication potential. In other words, continuous CC action can functionally CURE HIV infected cells, leaving the cells with a graveyard of inactivated HIV proviruses. This surprise finding represents a major hallmark in HIV CURE studies. We now propose to first delineate the underlying mechanisms and variables that determine the outcome of CC attack (HIV excision versus hypermutation). This will allow us to formulate the best CURE strategy. At the same time we focus on the major obstacle towards a CURE: delivery of the gene therapeutics to cells that compose the HIV-reservoir. The CC and delivery tools will then be combined for in vivo CURE studies in the HIS mouse.